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Homeostatic control of B lymphocyte subsets

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Abstract

Lymphocyte homeostasis poses a multi-faceted biological puzzle, because steady pre-immune populations must be maintained at an acceptable steady state to yield effective protection, despite stringent selective events during their generation. In addition, activated, memory and both short- and long-term effectors must be governed by independent homeostatic mechanisms. Finally, advancing age is accompanied by substantial changes that impact the dynamics and behavior of these pools, leading to cumulative homeostatic perturbations and compensation. Our laboratory has focused on the overarching role of BLyS family ligands and receptors in these processes. These studies have led to a conceptual framework within which distinct homeostatic niches are specified by BLyS receptor signatures, which define the BLyS family ligands that can afford survival. The cues for establishing these receptor signatures, as well as the downstream survival mechanisms involved, are integrated with cell extrinsic inputs via cross talk among downstream mediators. A refined understanding of these relationships should yield insight into the selection and maintenance of B cell subsets, as well as an appreciation of how homeostatic mechanisms may contribute to immunosenescence.

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References

  1. Miller JP, Stadanlick JE, Cancro MP. Space, selection, and surveillance: setting boundaries with BLyS. J Immunol. 2006;176:6405–10.

    PubMed  CAS  Google Scholar 

  2. Torres RM, Flaswinkel H, Reth M, Rajewsky K. Aberrant B cell development and immune response in mice with a compromised BCR complex. Science. 1996;272:1804–8.

    Article  PubMed  CAS  Google Scholar 

  3. Lam KP, Kuhn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell. 1997;90:1073–83.

    Article  PubMed  CAS  Google Scholar 

  4. Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3.

    Article  PubMed  CAS  Google Scholar 

  5. Mackay F, Schneider P, Rennert P, Browning J. BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol. 2003;21:231–64.

    Article  PubMed  CAS  Google Scholar 

  6. Rolink A, Melchers F. B-cell development in the mouse. Immunol Lett. 1996;54:157–61.

    Article  PubMed  CAS  Google Scholar 

  7. Osmond DG, Rolink A, Melchers F. Murine B lymphopoiesis: towards a unified model. Immunol Today. 1998;19:65–8.

    Article  PubMed  CAS  Google Scholar 

  8. Allman DM, Ferguson SE, Lentz VM, Cancro MP. Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J Immunol. 1993;151:4431–44.

    PubMed  CAS  Google Scholar 

  9. Loder F, Mutschler B, Ray RJ, Paige CJ, Sideras P, Torres R, et al. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J Exp Med. 1999;190:75–89.

    Article  PubMed  CAS  Google Scholar 

  10. Allman D, Lindsley RC, DeMuth W, Rudd K, Shinton SA, Hardy RR. Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J Immunol. 2001;167:6834–40.

    PubMed  CAS  Google Scholar 

  11. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 1988;334:676–82.

    Article  PubMed  CAS  Google Scholar 

  12. Nemazee DA, Burki K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 1989;337:562–6.

    Article  PubMed  CAS  Google Scholar 

  13. Nossal G, Pike B. Evidence for the clonal abortion theory of B-lymphocyte tolerance. J Exp Med. 1975;141:904–17.

    PubMed  CAS  Google Scholar 

  14. Tiegs SL, Russell DM, Nemazee D. Receptor editing in self-reactive bone marrow B cells. J Exp Med. 1993;177:1009–20.

    Article  PubMed  CAS  Google Scholar 

  15. Gay D, Saunders T, Camper S, Weigert M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med. 1993;177:999–1008.

    Article  PubMed  CAS  Google Scholar 

  16. Gu H, Tarlinton D, Muller W, Rajewsky K, Forster I. Most peripheral B cells in mice are ligand selected. J Exp Med. 1991;173:1357–71.

    Article  PubMed  CAS  Google Scholar 

  17. Clarke SH, McCray SK. VH CDR3-dependent positive selection of murine VH12-expressing B cells in the neonate. Eur J Immunol. 1993;23:3327–34.

    Article  PubMed  CAS  Google Scholar 

  18. Reichlin A, Gazumyan A, Nagaoka H, Kirsch KH, Kraus M, Rajewsky K, et al. A B cell receptor with two Igalpha cytoplasmic domains supports development of mature but anergic B cells. J Exp Med. 2004;199:855–65.

    Article  PubMed  CAS  Google Scholar 

  19. Zubler RH. Naive and memory B cells in T-cell-dependent and T-independent responses. Springer Semin Immunopathol. 2001;23:405–19.

    Article  PubMed  CAS  Google Scholar 

  20. Mukhopadhyay A, Ni J, Zhai Y, Yu GL, Aggarwal BB. Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase. J Biol Chem. 1999;274:15978–81.

    Article  PubMed  CAS  Google Scholar 

  21. Shu HB, Hu WH, Johnson H. TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol. 1999;65:680–3.

    PubMed  CAS  Google Scholar 

  22. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56.

    Article  PubMed  CAS  Google Scholar 

  23. Kelly K, Manos E, Jensen G, Nadauld L, Jones DA. APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell death. Cancer Res. 2000;60:1021–7.

    PubMed  CAS  Google Scholar 

  24. Cancro MP. Peripheral B-cell maturation: the intersection of selection and homeostasis. Immunol Rev. 2004;197:89–101.

    Article  PubMed  CAS  Google Scholar 

  25. Yan M, Marsters SA, Grewal IS, Wang H, Ashkenazi A, Dixit VM. Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity. Nat Immunol. 2000;1:37–41.

    Article  PubMed  CAS  Google Scholar 

  26. Marsters SA, Yan M, Pitti RM, Haas PE, Dixit VM, Ashkenazi A. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr Biol. 2000;10:785–8.

    Article  PubMed  CAS  Google Scholar 

  27. Yan M, Brady JR, Chan B, Lee WP, Hsu B, Harless S, et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr Biol. 2001;11:1547–52.

    Article  PubMed  CAS  Google Scholar 

  28. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science. 2001;293:2111–4.

    Article  PubMed  CAS  Google Scholar 

  29. Hahne M, Kataoka T, Schroter M, Hofmann K, Irmler M, Bodmer JL, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med. 1998;188:1185–90.

    Article  PubMed  CAS  Google Scholar 

  30. Hymowitz SG, Patel DR, Wallweber HJ, Runyon S, Yan M, Yin J, et al. Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding. J Biol Chem. 2005;280:7218–27.

    Article  PubMed  CAS  Google Scholar 

  31. von Bulow GU, Bram RJ. NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science. 1997;278:138–41.

    Article  Google Scholar 

  32. Patel DR, Wallweber HJ, Yin J, Shriver SK, Marsters SA, Gordon NC, et al. Engineering an APRIL-specific B cell maturation antigen. J Biol Chem. 2004;279:16727–35.

    Article  PubMed  CAS  Google Scholar 

  33. Pelletier M, Thompson JS, Qian F, Bixler SA, Gong D, Cachero T, et al. Comparison of soluble decoy IgG fusion proteins of BAFF-R and BCMA as antagonists for BAFF. J Biol Chem. 2003;278:33127–33.

    Article  PubMed  CAS  Google Scholar 

  34. Wu Y, Bressette D, Carrell JA, Kaufman T, Feng P, Taylor K, et al. Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS. J Biol Chem. 2000;275:35478–85.

    Article  PubMed  CAS  Google Scholar 

  35. Ingold K, Zumsteg A, Tardivel A, Huard B, Steiner QG, Cachero TG, et al. Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med. 2005;201:1375–83.

    Article  PubMed  CAS  Google Scholar 

  36. Bossen C, Cachero TG, Tardivel A, Ingold K, Willen L, Dobles M, et al. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood. 2008;111:1004–12.

    Article  PubMed  CAS  Google Scholar 

  37. Hsu BL, Harless SM, Lindsley RC, Hilbert DM, Cancro MP. Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. J Immunol. 2002;168:5993–6.

    PubMed  CAS  Google Scholar 

  38. Harless SM, Lentz VM, Sah AP, Hsu BL, Clise-Dwyer K, Hilbert DM, et al. Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers. Curr Biol. 2001;11:1986–9.

    Article  PubMed  CAS  Google Scholar 

  39. Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR, Shu HB, et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity. 2004;20:441–53.

    Article  PubMed  CAS  Google Scholar 

  40. Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004;20:785–98.

    Article  PubMed  CAS  Google Scholar 

  41. Hondowicz BD, Alexander ST, Quinn WJIII, Pagan AJ, Metzgar MH, Cancro MP, et al. The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. Int Immunol. 2007;19:465–75.

    Article  PubMed  CAS  Google Scholar 

  42. Sasaki Y, Casola S, Kutok JL, Rajewsky K, Schmidt-Supprian M. TNF family member B cell-activating factor (BAFF) receptor-dependent and-independent roles for BAFF in B cell physiology. J Immunol. 2004;173:2245–52.

    PubMed  CAS  Google Scholar 

  43. Enzler T, Bonizzi G, Silverman GJ, Otero DC, Widhopf GF, Anzelon-Mills A, et al. Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease. Immunity. 2006;25:403–15.

    Article  PubMed  CAS  Google Scholar 

  44. Hatada EN, Do RK, Orlofsky A, Liou HC, Prystowsky M, MacLennan IC, et al. NF-kappa B1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-kappa B2 p100 to p52 in quiescent mature B cells. J Immunol. 2003;171:761–8.

    PubMed  CAS  Google Scholar 

  45. Huang X, Di Liberto M, Cunningham AF, Kang L, Cheng S, Ely S, et al. Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1. Proc Natl Acad Sci USA. 2004;101:17789–94.

    Article  PubMed  CAS  Google Scholar 

  46. Stadanlick JE, Cancro MP. BAFF and the plasticity of peripheral B cell tolerance. Curr Opin Immunol. 2008;20:158–61.

    Article  PubMed  CAS  Google Scholar 

  47. Stadanlick JE, Cancro MP. Unraveling the warp and weft of B cell fate. Immunity. 2006;25:395–6.

    Article  PubMed  CAS  Google Scholar 

  48. Miller DJ, Hayes CE. Phenotypic and genetic characterization of a unique B lymphocyte deficiency in strain A/WySnJ mice. Eur J Immunol. 1991;21:1123–30.

    Article  PubMed  CAS  Google Scholar 

  49. Miller DJ, Hanson KD, Carman JA, Hayes CE. A single autosomal gene defect severely limits IgG but not IgM responses in B lymphocyte-deficient A/WySnJ mice. Eur J Immunol. 1992;22:373–9.

    Article  PubMed  CAS  Google Scholar 

  50. Rahman ZS, Manser T. B cells expressing Bcl-2 and a signaling-impaired BAFF-specific receptor fail to mature and are deficient in the formation of lymphoid follicles and germinal centers. J Immunol. 2004;173:6179–88.

    PubMed  CAS  Google Scholar 

  51. Castigli E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan AK, et al. Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci USA. 2004;101:3903–8.

    Article  PubMed  CAS  Google Scholar 

  52. Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med. 2005;201:35–9.

    Article  PubMed  CAS  Google Scholar 

  53. von Bulow GU, van Deursen JM, Bram RJ. Regulation of the T-independent humoral response by TACI. Immunity. 2001;14:573–82.

    Article  Google Scholar 

  54. Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T, et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol. 2001;2:638–43.

    Article  PubMed  CAS  Google Scholar 

  55. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199:91–8.

    Article  PubMed  CAS  Google Scholar 

  56. Treml LS, Crowley JE, Cancro MP. BLyS receptor signatures resolve homeostatically independent compartments among naive and antigen-experienced B cells. Semin Immunol. 2006;18:297–304.

    Article  PubMed  CAS  Google Scholar 

  57. Treml LS, Carlesso G, Hoek KL, Stadanlick JE, Kambayashi T, Bram RJ, et al. TLR stimulation modifies BLyS receptor expression in follicular and marginal zone B cells. J Immunol. 2007;178:7531–9.

    PubMed  CAS  Google Scholar 

  58. Cancro MP, Allman DM. Connecting the dots: revealing the interactions of lymphocyte development and homeostasis in the immunobiology of aging. Semin Immunol. 2005;17:319–20.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 284 John Morgan Building 36th and Hamilton Walk, Philadelphia, PA, 19104-6082, USA

    Jenni E. Crowley, Jean L. Scholz, William J. Quinn III, Jason E. Stadanlick, John F. Treml, Laura S. Treml, Yi Hao, Radhika Goenka, Patrick J. O’Neill, Andrew H. Matthews, Ronald F. Parsons & Michael P. Cancro

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  1. Jenni E. Crowley
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  2. Jean L. Scholz
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  3. William J. Quinn III
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  4. Jason E. Stadanlick
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  5. John F. Treml
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  6. Laura S. Treml
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  7. Yi Hao
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  12. Michael P. Cancro
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Correspondence to Michael P. Cancro.

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Crowley, J.E., Scholz, J.L., Quinn III, W.J. et al. Homeostatic control of B lymphocyte subsets. Immunol Res 42, 75–83 (2008). https://doi.org/10.1007/s12026-008-8036-y

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